It has been found in the recent investigations that pseudolaric acids and the compounds with correlative structures possess important biological activities. The methods for the isolation of such compounds and the pharmacologically experimental results have been disclosed in the following references:
1. Wu Saoxi, et al., Chinese Journal of Dermatology, 1960 (8): 18;
2. Li Zhulian, Zhou Bingnan, et al., “The proceeding of sino-American symposium on chemistry of Natural products”, <<Chemistry of Natural Products>> (1982), pp.150-155;
3. Li Zhulian, Xu Guangyi, et al., “Study of new diterpenoids from pseudolarix kaempferi”, Acta Chimica Sinica, 1982 (40): 447-456;
4. Wang Weichen, et al., “Action of anti-procreation of pseudolaric acid-B”, Acta Pharmacol. Sinica, 1982 (3): 188-192;
5. Erguang Li, Alice M. Clark and Charles D. Hufford, “Antifugal evaluation of Pseudolaric acid B, a major constituent of pseudolarix kaempferi”, Journal of Natural Product, 1995 (58): 57-67;
6. De-Ji Pan, Zhu-lian Li, et al., “The cytotoxic principles of pseudolarix kaempferi: Pseudolaric acid-A and -B and related derivatives”, Plant Medica, 1990 (56): 383-385.
All the literatures mentioned above are incorporated herewith for reference.
It was reported that the angiogenesis in the tumor tissues was related with the malignant proliferation and metastasis of the tumor. The inhibition of tumor angiogenesis will lead to the decrease of supplies of oxygen and nutrition which were necessary for the tumor growth, then the tumor proliferation will be inhibited. Meantime, anti-angiogenesis also prevents the tumor metastasis because it can block the pathway through which tumor cells can enter into the blood circulation from tumor tissue via neonate capillaries.
The literatures in respect to the relationship between angiogenesis and cancers were listed as follows:
1. Cockerill G. W., Gamble T. R., Vadas M. A., “Angiogenesis: models and modulators”, Int. Rev. Cytol., Vol.159(1995), pp.113-160;
2. Senger D. R., Van de water L., Brown L. F., et al., “Vascular permeability factor(VPF, VEGF) in tumor biology”, Cancer Metastasis Rev., Vol.12(1993), pp.303-324;
3. Donovan D., Harmey J. H., Redmond H. P. et al., “Ascites revisited: a novel role for tamoxifen”, Eur. J. Surg. Oncol., Vo.123(1997), pp. 570;
4. Ingber D, Fujita T., Kishimoto S. et al., “Synthetic analogues of fumagillin that inhabit angiogenesis and suppress tumor growth”, Nature, Vol.348 (1990), pp. 555-560;
5. Jiang W. G., Puntis M. C. A., Hallett M. B., “molecular and cellular basis of cancer invasion and metastasis: implications for treatment”, Br. J. Surg., Vol.81 (1994), pp. 1576-1590;
6. Fidle I. J., Gerstein D. M., Hart I. R., “The biology of cancer invasion and metastasis”, Adv. Cancer Res., Vol.28(1978), pp.149-250;
7. Hanahan D., Folkman J., “Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis”, Cell., Vol.86(1996), pp. 353-364;
8. Ferrara N., “The role of vascular endothelial growth factor in pathological angiogenesis”, Breast Cancer Res. Treat, Vol.36(1995), pp. 127-137;
9. O'Reilly M., Holmgren L., Shing Y., et al., “Angiostain: anovel angenesis inhabitor that medicates the suppression of metastases by a Lewis lung carcinoma”, Cell., Vol.79 (1994), pp. 689-692;
10. O'Reilly M. S., Holmgren L., Chen C., et al., “Angiostatin induces and sustains domancy of human primary tumors in mice”, Nature Med., Vol.2 (1996), pp.689-692;
11. O'Reilly M. S., Boehm J., Shing Y., et al., “Endosatatin: an endogenous inhabitator of angiogenesis and tumor growth”, Cell., Vol.88 (1997), pp. 277-285;
12. Frank R. E., Saclarides T. J., Sue Leurgans, et al., “Tumor angiogenesis as a predictor of recurrence and survival in patients with node-negative colon cancer”, Ann. Surg., Vol.222 (1995), pp. 695-699.
All the literatures mentioned above are incorporated herewith for reference.
Although it was known that the use of angiogenesis inhibitors in the cancer chemotherapy could increase therapeutic effects and prevent the metastasis and relapse of the tumor, but no new drug targeting at angiogenesis has been marketed nowadays.
During long-time researches, the inventors have found that pseudolaric acids and new derivatives thereof could inhibit the growth of human microvascular endothelial cells, thus they could decrease supplies of oxygen and nutrition, which were necessary for tumor cells, by inhibiting the formation of blood vessels in the tumor tissue. Thereby, the cleavage and proliferation of tumor cells would be inhibited, resulting in the atrophy and vanishing of the tumor.
Accordingly, one purpose of the invention is to provide novel pseudolaric acid derivatives.
Another purpose of the invention is to provide a process for preparing said derivatives.
A further purpose of the invention is to provide antitumor or antifungal pharmaceutical compositions containing the same.